The majority of his ministry was dedicated to fighting against the Arian heresy. Arius, a priest of Alexandria, claimed Jesus was not truly God and that there was a time when the Son, the second person of the Trinity, did not exist.

The bishop was gentle with Arius but when Arianism started accumulating a larger following, Alexander finally excommunicated Arius. The sentence of excommunication was confirmed in the year 320.

Alexander's epistle on the Arian heresy has survived and remains an important part of ecclesiastical literature.

It is assumed that St. Alexander drew up the acts of the first General Council of Nicaea in 325, where Arianism was formally condemned.

He died in Alexandria two years after his return from the council.

St. Alexander was also famous for his charity to the poor and his doctrine on life.